The diagnostic criteria for pediatric mastocytosis are largely based on adult studies. We thus evaluated use of the WHO criteria for diagnosis of systemic disease in pediatric mastocytosis. One hundred and thirteen children with pediatric mastocytosis were evaluated. Complete bone marrow evaluations were performed in 50 cases. Marrows were analyzed by histopathology, flow cytometry, and for KIT D816V. Bone marrow biopsies displayed mild atypical hematopoietic maturation. There was no evidence of peripheral blood cytopenias, myelodysplastic syndrome, myeloproliferative neoplasm or leukemia within this cohort. Based on these observations, we reached the conclusion that WHO criteria are applicable to the diagnosis of systemic mastocytosis in the pediatric population. Although unsuspected bone marrow findings typically seen in myeloproliferative disorders were observed, children within this study remained clinically stable without progression to a more aggressive variant. We similarly examined clinical aspects of pediatric mastocytosis in relationship to serum tryptase and bone marrow pathology to provide practical guidance for management. In children with high tryptase and severe mediator symptoms, all with organomegaly had systemic disease; none without organomegaly had systemic disease. Serum tryptase values differed significantly between urticaria pigmentosa, diffuse cutaneous, and systemic mastocytosis, and in all three categories versus controls. Tryptase levels in most cases declined with time as did symptoms, and highly correlated with mast cell percent within the bone marrow of patients with systemic disease. Within our cohort, children within all categories of disease either remained stable or improved. Organomegaly was a strong indicator of who needed a bone marrow biopsy. Serum tryptase reflected bone marrow findings and sequential tryptase determinations were useful in supplementing clinical judgment as to disease course. Because SM results from a mutation in c-kit in mast cells, we questioned if the function of bone marrow stromal cells (BMSCs; also known as mesenchymal stem cells) might be affected by the invasion of bone marrow by mutant mast cells. In our patients, BMSCs from SM patients did not have a mutation in c-kit, but they proliferated poorly and osteogenic differentiation was deficient. Since the hematopoietic supportive abilities of BMSCs are also important, we studied the engraftment in NSG mice of human CD34(+) hematopoietic progenitors, after being co-cultured with BMSCs of healthy volunteers vs. BMSCs derived from patients with SM. BMSCs derived from the bone marrow of patients with SM were deficient in support of hematopoiesis. We also found significant differences between healthy and SM derived BMSCs in the expression of genes with a variety of functions, including the WNT signaling, ossification, and bone remodeling. These observations suggest that some findings associated with SM might be driven by epigenetic changes in BMSCs caused by dysfunctional mast cells in the bone marrow compartment. We also participated in two initiatives directly dealing with patient care issues. First, we participated in an international task force charged to up-date the classification of forms of cutaneous mastocytosis. This resulted in revised definitions and criteria for forms of mastocytosis in the skin. In particular, the typical maculopapular cutaneous lesions (urticaria pigmentosa) were subdivided into two variants, a monomorphic variant with small maculopapular lesions, typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, typically observed in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. Refinements also resulted in the removal of teleangiectasia macularis eruptive perstans from the current classification of cutaneous mastocytosis and removal of solitary from the term mastocytoma. In a second initiative, we assisted in the development of the first mastocytosis quality of life questionnaire for adult patients with cutaneous and indolent systemic mastocytosis. This instrument will serve as a much needed measure of response to medical intervention in future clinical studies and in routine patient care.